RUI: Understanding Steroid Regulation of Ionotropic Glutamate Receptors

智力的优点神经元之间的交流是由许多机制来调节的。 谷氨酸是中枢神经系统中主要的快速兴奋性神经递质，其主要靶点之一是位于突触后神经膜上的离子型谷氨酸受体（iGluRs）。 离子型谷氨酸受体是配体门控离子通道家族，其包括AMPA、红藻氨酸和NMDA受体。 当与谷氨酸结合时，非选择性阳离子通道的开放允许正电荷的流入，导致突触后细胞去极化，从而传播动作电位。 这些受体受到严格的调控。 结构上非常相似的内源性硫酸化类固醇，硫酸双烯醇酮和硫酸双烯醇酮，已被证明差异调节这些受体。Gentile实验室以前的研究表明，这些类固醇依赖于iGluR家族成员与两个胞外结构域之一结合。 利用这个平台，高分辨率结构研究，计算研究和突变分析的组合现在将允许在详细的分子水平上理解这种调节。 目的是了解哪些结合事件和构象变化导致iGluR通道的开放（和动作电位的传播），以及哪些导致其关闭。更广泛的影响该项目的更广泛的影响集中在激发和培养下一代学生在科学发现的过程中。 这项研究将提供高质量的，以结果为导向的，跨学科的培训，在里士满大学（UR）的本科生。 此外，它将涉及高中化学和生物教师在里士满，弗吉尼亚州在调查为基础的调查，这将使他们能够开发范围从生物物理学到分子生物学的新技术，收集的想法纳入新的课程或实验室，赚取专业发展点，并介绍他们到UR教师，可以作为未来的导师。 它还将让高中生参与暑期研究，这将使他们能够发展批判性思维和解决问题的技能，并使他们接触到科学的兴奋。

Intellectual MeritThere are many mechanisms by which communication between neurons is regulated. Glutamate, the major fast excitatory neurotransmitter in the central nervous system, has, as one of its prime targets, the ionotropic glutamate receptors (iGluRs) which reside in the postsynaptic neural membrane. Ionotropic glutamate receptors are a family of ligand gated ion channels, which include AMPA, kainate, and NMDA receptors. Upon binding to glutamate, the opening of a nonselective cation channel allows an influx of positive charge, leading to postsynaptic cell depolarization, and hence propagation of the action potential. These receptors are carefully regulated. The endogenous sulfated steroids, pregnenolone sulfate and pregnenolone sulfate, which are structurally very similar, have been shown to differentially regulate these receptors. Previous research from the Gentile lab has shown that these steroids bind to one of two extracellular domains, dependant upon the iGluR family member. Using this as a platform, a combination of high resolution structural studies, computational studies, and mutational analysis will now allow for an understanding of this regulation on a detailed molecular level. The goal is to understand which binding events and conformational changes lead to an opening of the iGluR channel (and propagation of the action potential) and which lead to its closing.Broader Impacts The broader impacts of this project are focused both on exciting and training the next generation of students in the process of scientific discovery. This research will provide high quality, outcome-oriented, interdisciplinary training to undergraduates at the University of Richmond (UR). In addition, it will involve high school chemistry and biology teachers in Richmond, VA in an inquiry based investigation, which will enable them to develop new techniques ranging in scope from biophysics to molecular biology, gather ideas to incorporate into new courses or labs, earn professional development points, and introduce them to UR faculty that can serve as future mentors. It will also involve high school students in summer research, which will allow them to develop critical thinking and problem solving skills, as well as to expose them to the excitement of science.